CN107400036A - A kind of method of synthesis 1,2- dimethylene cyclobutane chipal compounds - Google Patents

A kind of method of synthesis 1,2- dimethylene cyclobutane chipal compounds Download PDF

Info

Publication number
CN107400036A
CN107400036A CN201610335358.9A CN201610335358A CN107400036A CN 107400036 A CN107400036 A CN 107400036A CN 201610335358 A CN201610335358 A CN 201610335358A CN 107400036 A CN107400036 A CN 107400036A
Authority
CN
China
Prior art keywords
formula
compound
phenyl
sample
rhodium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201610335358.9A
Other languages
Chinese (zh)
Other versions
CN107400036B (en
Inventor
康强
郑伟锋
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujian Institute of Research on the Structure of Matter of CAS
Original Assignee
Fujian Institute of Research on the Structure of Matter of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujian Institute of Research on the Structure of Matter of CAS filed Critical Fujian Institute of Research on the Structure of Matter of CAS
Priority to CN201610335358.9A priority Critical patent/CN107400036B/en
Priority to PCT/CN2016/085058 priority patent/WO2017197670A1/en
Publication of CN107400036A publication Critical patent/CN107400036A/en
Application granted granted Critical
Publication of CN107400036B publication Critical patent/CN107400036B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/40—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing only non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

This application discloses a kind of method of 1,2 dimethylene cyclobutane chipal compounds of synthesis, in the presence of rhodium complex, 1,2 dimethylene cyclobutane chipal compounds are synthesized by connection enamine compound.This method can be under gentle reaction condition, the dimethylene cyclobutane chipal compounds of synthesis 1,2 of high efficiency, high enantioselectivity and highly-solid selectively.

Description

A kind of method of synthesis 1,2- dimethylene cyclobutane chipal compounds
Technical field
The application is related to a kind of method of synthesis 1,2- dimethylene cyclobutane chipal compounds, belongs to natural products and medicine Thing field.
Background technology
Cyclobutane derivative compound has critical role in many natural products and drug molecule.And ring fourth is synthesized at present The method of alkane mainly synthesizes cyclobutane by alkene, alkynes, connection alkene and other unsaturated systems by [2+2] cycloaddition.Closely Nian Lai, the method for cyclobutane is synthesized making alkene or connection alkene that [2+2] cycloaddition occur with other unsaturated systems by heating Through largely being studied, but the bad, reaction temperature of selectivity to be present high (being typically larger than 200 DEG C) for such reaction, during reaction Between long (be typically larger than 72h) the shortcomings that.
As the method for [2+2] cycloaddition synthesis cyclobutane makes progress in photocatalysis field, [the 2+ on metal catalytic 2] cycloaddition synthesis cyclobutane method gradually increase, wherein report on gold [Angew.Chem.Int.Ed.2009,48, 4532-4535；Org.Lett.2012,14,436-439.], palladium [J.Am.Chem.Soc.2000,122,11529-11530； Angew.Chem.Int.Ed.2006,45,8009-8013.], nickel [J.Am.Chem.Soc.1985,107,3160-3172； J.Am.Chem.Soc.1988,110,8494-8500；J.Am.Chem.Soc.1989,111,3761-3762； J.Am.Chem.Soc.2000,122,10776-10780.], the metal such as copper [Org.Lett.2012,14,1366-1369.] Catalytic reaction.The reaction of metal catalytic is remarkably improved regioselectivity and stereoselectivity.
At present, the method that chiral cyclobutane is prepared with connection enamine [2+2] cycloaddition of rhodium catalysis not yet has been reported that.
The content of the invention
The purpose of the application is to provide a kind of method of synthesis 1,2- dimethylene cyclobutane chipal compounds.Match somebody with somebody in rhodium In the presence of body thing, 1,2- dimethylene cyclobutane chipal compounds are synthesized by connection enamine compound.This method can be gentle Reaction condition under, the synthesis 1 of high efficiency, high enantioselectivity and highly-solid selectively, 2- dimethylene cyclobutane chiralityizations Compound.
The method of the synthesis 1,2- dimethylene cyclobutane chipal compounds, it is characterised in that in depositing for rhodium complex Under, 1,2- dimethylene cyclobutane chipal compounds are synthesized by connection enamine compound；
The rhodium complex is formed by the rhodium source containing rhodium element with part；The part is chiral ligand and/or non-hand Property part；The chiral ligand and achiral ligand are selected from the organic compound containing P elements and/or nitrogen extremely Few one kind；
The enamine compound, which is selected from, has at least one of compound of chemical structural formula shown in Formulas I：
The 1,2- dimethylenes cyclobutane chipal compounds are the compounds with the chemical structural formula as shown in Formula II -1 And/or the compound with the chemical structural formula as shown in Formula II -2：
In Formulas I, Formula II -1 and Formula II -2, R1、R2Independently selected from the aliphatic group of hydrogen, carbon number no more than 18, have The group of structural formula shown in formula III, the group with structural formula shown in Formula IV, the group with structural formula shown in Formula V, with formula The group of structural formula shown in VI or the group with structural formula shown in Formula VII：
In formula III, R3It is no more than 18 substituted fatty hydrocarbon selected from aliphatic group of the carbon number no more than 18, carbon number Base, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroarylalkyl, substitution heteroarylalkyl；
R4- A- formula IVs
In formula IV, A is selected from the alkylene that carbon number is no more than 10；R4It is no more than 18 aliphatic hydrocarbon selected from carbon number The substituted fatty hydrocarbon base of base, carbon number no more than 18, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substitution Aralkyl, heteroarylalkyl, substitution heteroarylalkyl, silylation；
R5- O-B- Formula V
In Formula V, B is selected from the alkylene no more than 10 from carbon number；R5It is no more than 18 aliphatic hydrocarbon selected from carbon number The substituted fatty hydrocarbon base of base, carbon number no more than 18, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substitution Aralkyl, heteroarylalkyl, substitution heteroarylalkyl, silylation；
In Formula IV, R6It is no more than 18 substituted fatty hydrocarbon selected from aliphatic group of the carbon number no more than 18, carbon number Base, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroarylalkyl, substitution heteroarylalkyl, silicon Alkyl；
In Formula VII, R7It is no more than 18 substituted fatty hydrocarbon selected from aliphatic group of the carbon number no more than 18, carbon number Base, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroarylalkyl, substitution heteroarylalkyl, silicon Alkyl.
Substituted fatty hydrocarbon base of the carbon number no more than 18 is substituted by least one hydrogen atom on aliphatic group Base substitutes formed group；Preferably, the substituent on the substituted fatty hydrocarbon base is in nitro, amino, F, Cl, Br, I At least one.
The substituted aryl is that at least one hydrogen atom is substituted with a substituent formed group on the aromatic rings by aryl； Preferably, the substituent on the substituted aryl be selected from carbon number no more than 18 aliphatic group, nitro, amino, F, Cl, At least one of Br, I.
The substituted heteroaryl is that at least one hydrogen atom is substituted with a substituent what is formed on the hetero-aromatic ring by heteroaryl Group；Substituent on the substituted heteroaryl be selected from aliphatic group of the carbon number no more than 18, nitro, amino, F, Cl, At least one of Br, I.
As a kind of preferable scheme of the application, in Formulas I and Formula II, R1、R2Independently selected from carbon number no more than 18 Aliphatic group, acetyl group (being abbreviated as Ac), benzyl (being abbreviated as Bn), 1- menaphthyls, 4- methoxy-benzyls, tert-butyldimethyl silyl Oxygen ethyl, 3,3- diphenyl propyls, 2- phenethyls, furfuryl, thienylethyl, indolylethyl, 1,3- benzo dioxy -5- first Base, tertbutyloxycarbonyl (being abbreviated as Boc), benzoyl (being abbreviated as Bz), tablet held before the breast by officials methoxycarbonyl group (being abbreviated as Fmoc), tri-chloroethoxy base Formoxyl (being abbreviated as Troc), p-nitrophenyl sulfonyl, Methyl benzenesulfonyl base (being abbreviated as TS) or methyl sulphonyl (are abbreviated as MS)。
As a kind of preferable scheme of the application, R1And R2In it is at least one be selected from structural formula shown in formula III base Group.It is further preferred that R1And R2In it is at least one be p-nitrophenyl sulfonyl, to Methyl benzenesulfonyl base or methyl sulphonyl.
As a kind of preferable scheme of the application, R1And R2One of them is selected from the group with structural formula shown in formula III. It is further preferred that R1And R2One of them is p-nitrophenyl sulfonyl, to Methyl benzenesulfonyl base or methyl sulphonyl.
Those skilled in the art, suitable rhodium Base Metal organic compound can be selected as rhodium source according to being actually needed.It is excellent Selection of land, the rhodium source are selected from dimerization rhodium acetate [Rh (CH3COO)]2, triphenylphosphine rhodium carbonyl chloride Rh (PPh3) Cl (CO), dimerization Close hydroxyl (1,5- cyclo-octadiene) rhodium (I) [Rh (COD) OH]2, praseodynium rhodium (III) Rh (CH3COCHCOCH3)3, four carbonyls The rhodium of base dichloride two [Rh (CO)2Cl]2, (1,5- cyclo-octadiene) chlorine rhodium (I) dimer [Rh (COD)2Cl]2, the rhodium of dichloride two (double down borneol diene) [Rh (NBD) Cl]2, acetylacetone,2,4-pentanedione bi-vinyl rhodium Rh (acac) (C2H4)2, (1,5- rings are pungent for acetylacetone,2,4-pentanedione Diene) rhodium Rh (acac) (COD), trifluoroacetic acid rhodium (II) dimer Rh2(CF3COO)4, four or three [- (+)-N- is (to dodecyl Benzene sulfonyl) porphyrin] two rhodium Rh2(R-DOSP)4, dichloro (pentamethylcyclopentadiene base) close rhodium dimer (Cp*RhCl2)2, triphen Base phosphine hydrogenized carbonyl rhodium Rh (PPh3At least one of) H (CO).
As a kind of embodiment, the part is achiral ligand, selected from the chemical combination with structural formula shown in formula (1) The compound of structural formula shown in thing, formula (2), the compound of structural formula shown in formula (3), compound, the formula of structural formula shown in formula (4) (5) at least one of compound of structural formula shown in the compound of structural formula shown in, formula (6)：
In formula (1), R8Selected from hydrogen ,-CH3、—OCH3、—N(CH3)2、—OCH(CH3)2；R9Selected from hydrogen ,-OCH3、—N (CH3)2、—OCH(CH3)2；R10Selected from cyclohexyl ,-C (CH3)3；
In formula (2), R11Selected from-OCH2CH3、—C(CH3)3, phenyl；
In formula (3), R12Selected from phenyl, cyclohexyl；N is 1 or 3；
In formula (4), R13Selected from phenyl ,-C (CH3)3；
In formula (5), R14Selected from hydrogen, phenyl ,-CH3；R15Selected from hydrogen ,-CH3、—C(CH3)3；
In formula (6), R16Selected from-CH3Or-COOH.
As a kind of embodiment, the part is chiral ligand, selected from the compound of structural formula shown in formula (7), The compound of structural formula shown in formula (8), the compound of structural formula shown in formula (9), compound, the formula of structural formula shown in formula (10) (11) compound, the formula of the compound of structural formula shown in the compound of structural formula shown in, formula (12), structural formula shown in formula (13) (14) compound, the formula of the compound of structural formula shown in the compound of structural formula shown in, formula (15), structural formula shown in formula (16) (17) compound, the formula of the compound of structural formula shown in the compound of structural formula shown in, formula (18), structural formula shown in formula (19) (20) at least one of compound of structural formula shown in：
In formula (7), R17Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3, 5- 3,5-dimethylphenyls, p-nitrophenyl；R18Selected from methyl, phenyl, the tert-butyl group, isopropyl, cyclohexyl；
In formula (8), R19Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3, 5- 3,5-dimethylphenyls, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (9), R20Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3, 5- 3,5-dimethylphenyls, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (10), R21Selected from methyl, phenyl, trifluoromethy phenyl；R22Selected from methyl, phenyl, trifluoromethy benzene Base, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- 3,5-dimethylphenyls, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (11), R23Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- 3,5-dimethylphenyls, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (12), R24Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- 3,5-dimethylphenyls, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (13), R25Selected from H, F；R26Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- Trimethylphenyl, 3,5- 3,5-dimethylphenyls, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (18), R27Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- 3,5-dimethylphenyls, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (19), R28Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- 3,5-dimethylphenyls, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (20), R29Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- 3,5-dimethylphenyls, p-nitrophenyl, isopropyl, cyclohexyl.
When part is achiral ligand, 1, the 2- dimethylenes cyclobutane chipal compounds are that have such as the institute of Formula II -1 Show that the compound of chemical structural formula and the compound mole ratio example with the chemical structural formula as shown in Formula II -2 are 1:1 mixing Thing；I.e. products therefrom is racemic product.
When part is chiral ligand, 1, the 2- dimethylenes cyclobutane chipal compounds mainly have such as Formula II -1 The compound of shown chemical structural formula；I.e. products therefrom has optical activity.
Preferably, the achiral ligand is selected from the compound of structural formula shown in formula (4).
Preferably, the chiral ligand is selected from the compound of structural formula shown in formula (12).
As the application preferred embodiment, the method for the synthesis 1,2- dimethylene cyclobutane chipal compounds, Including at least following steps：
A) rhodium source, chirality and/or achiral ligand, connection enamine compound are added in organic solvent, in -78 DEG C to 120 Stirring reaction 10 minutes to 120 hours at DEG C；
B) after reaction terminates, add water quenching to go out, through liquid separation, washing, drying, removing organic solvent, separation, produce described 1,2- Dimethylene cyclobutane chipal compounds.
The reaction equation of the synthesis 1,2- dimethylene cyclobutane chipal compounds methods is as follows：
Preferably, reaction temperature is -20 DEG C to 100 DEG C in step a).It is further preferred that reaction temperature is in step a) 0 DEG C to 100 DEG C.It is further preferred that reaction temperature is 20 DEG C to 100 DEG C in step a).
Preferably, the reaction time is 10 minutes to 48 hours in step a).It is further preferred that the reaction time in step a) For 10 minutes to 10 hours.It is further preferred that the reaction time is 30 minutes to 8 hours in step a).
Preferably, connection enamine compound and the molar ratio in rhodium source and part are in step a)：
Join enamine compound：Rh：Part=1：0.01~1：0.01~1；
The molal quantity in the rhodium source is in terms of the molal quantity of rhodium element contained in rhodium source.
It is further preferred that connection enamine compound and the molar ratio in rhodium source and part are in step a)：
Join enamine compound：Rh：Part=1：0.01~0.15：0.05~0.50.
Those skilled in the art can be according to being actually needed, the addition selected from organic solvent.Preferably, organic solvent adds Enter amount is with the ratio for joining enamine compound：In 1L organic solvent join enamine compound molal quantity for 0.05mol~ 0.5mol。
Preferably, organic solvent described in step a) is selected from benzene, carbon tetrachloride, petroleum ether, tetrahydrofuran, dimethyl formyl Amine, acetone, ether, dichloromethane, chloroform, toluene, dimethylbenzene, chlorobenzene, o-dichlorohenzene, hexamethylene, n-hexane, positive heptan At least one of alkane, the ring of dioxane six, acetonitrile, methanol, ethanol, pentane.
Preferably, the method for the step b) separation in recrystallization, thin-layer chromatography, column chromatography, vacuum distillation extremely Few one kind.
Preferably, in the recrystallization, thin-layer chromatography and column chromatography method, used solvent is polar solvent and non-pole The mixture of property solvent；Wherein, the volume ratio of polar solvent and non-polar solven is 1：0.1~500.It is further preferred that institute State in recrystallization, thin-layer chromatography and column chromatography method, used solvent is selected from the mixture of dichloromethane-n-hexane, isopropyl The mixture of alcohol-petroleum ether, the mixture of ethyl acetate-light petrol, the mixture of ethyl acetate-hexane, isopropanol-acetic acid Any one in the mixture of ethyl ester-petroleum ether.It is further preferred that recrystallization, thin-layer chromatography and the column chromatography side In method, used solvent is selected from ethyl acetate/petroleum ether volume ratio=1：The mixing of 0.1~50 ethyl acetate-light petrol Thing, isopropanol/petroleum ether volume ratio=1：The mixture of 0.1~500 isopropanol-petroleum ether.
In the application, " aliphatic group " is the base formed by losing any one hydrogen atom on aliphatic hydrocarbon compound molecule Group.The aliphatic hydrocarbon compound does not contain aromatic rings or hetero-aromatic ring, including alkane compound, the olefinic compound containing C=C double bonds Thing, the simultaneously acetylene hydrocarbon compound containing the keys of C ≡ C three, the unsaturated hydrocarbon compound containing C=C double bonds and the keys of C ≡ C three.This Shen Please in, " alkyl " is the group formed by losing any one hydrogen atom on alkane compound molecule.The alkane compound Including linear paraffin, branched paraffin, cycloalkane, the cycloalkane with side chain.In the application, " aryl " is aromatic compound point The group that a hydrogen atom is formed on aromatic rings is lost on son；The benzene formed as lost any one hydrogen atom on phenyl ring Base.In the application, " heteroaryl " is to contain the heteroatomic aromatic compound of O, N, S (abbreviation heteroaryl chemical combination in aromatic rings Thing) group that any one hydrogen atom is formed on aromatic rings is lost on molecule；As lost any one hydrogen atom on piperazine ring Formed piperazinyl.In the application, " aralkyl " is the aromatic compound containing alkyl substituent, and losing alkyl on molecule takes The group that the upper any hydrogen atoms of Dai Ji are formed；As toluene loses the benzyl that a hydrogen atom is formed on methyl." heteroaryl alkane Base " is containing containing the heteroatomic aromatic compound of O, N, S in alkyl substituent and aromatic rings, and losing alkyl on molecule takes The group that any one upper hydrogen atom of Dai Ji is formed；Such as 1,3- benzo dioxy -5- methyl.In the application, " alkylene " be by The group that any two hydrogen atom is formed is lost on hydrocarbon molecules；As methyl loses the methylene of two hydrogen atoms formation The group that two hydrogen atoms of contraposition are formed is lost on base, or phenyl ring.In the chemical formula or structure of the application, " Ph " is phenyl Write a Chinese character in simplified form；“tBu " is writing a Chinese character in simplified form for the tert-butyl group；" ac " is writing a Chinese character in simplified form for acetyl group；" acac " is writing a Chinese character in simplified form for levulinic ketone group；" Cp " is ring Pentadienyl is write a Chinese character in simplified form；" COD " is writing a Chinese character in simplified form for cyclo-octadiene base；" NBD " is bicycloheptadiene (alias:Norbornadiene) letter Write；" DOSP " is (to dodecyl benzene sulfonyl) that porphyryl is write a Chinese character in simplified form.
The beneficial effect of the application includes but is not limited to：
(1) method provided herein, to join enamine compound as Material synthesis 1,2- dimethylenes cyclobutane is chiral Compound, there is the advantages of efficiency high, enantioselectivity height and stereoselectivity is high.
(2) method provided herein, using rhodium complex as catalyst, reaction condition is gentle, simple to operate, production Thing separating-purifying is easy, and product yield high, purity are good.
Embodiment
The application is described in detail with reference to embodiment, but the application is not limited to these embodiments.
In embodiment, unless otherwise instructed, test condition is as follows：
Nuclear magnetic resoance spectrum1H-NMR and13C-NMR uses the type spectroscopes of 400AVANCE III of Brooker company (Bruker) (Spectrometer) determine, 400MHz, the deuterated methane CDCl of trichlorine3.Product analysis is detected using thin-layered chromatography, and solvent is The mixture of ethyl acetate and petroleum ether (volume ratio ethyl acetate/petroleum ether=1/5).Infrared spectrum analysis (IR) is using Germany The type ftir analysis instrument of TENSOR 27 of Brooker company.High resolution mass spectrum analysis HRMS flies using match is silent The LTQ FT Ultra system mass spectrographs of your scientific ＆ technical corporation (Thermo Fisher Scientific) of generation.Enantioselectivity Excessive value analysis uses Shimadzu Corporation (Shimadzu) high-efficient liquid phase chromatogram HPLC LC-20AD, and chiral column uses Daicel company (Daicel Chemical Industries, LTD) Chiralpak IA, IB, ID, IF post.Angle-of-rotation measuring uses Shanghai thing Light INESA SGW-1 automatic polarimeters.
In embodiment, the yield of 1,2- dimethylene cyclobutane chipal compounds is calculated by below equation：Yield =(quality of 1,2- dimethylene cyclobutane chipal compounds)/(connection enamine compound molal quantity × 1,2- dimethylene ring fourths The molal weight of alkane chipal compounds) × 100%.
In embodiment, double (1,5- cyclo-octadiene) radium chlorides are expressed as [Rh (COD) Cl]2。
The preparation of the product 1 of embodiment 1
Product 1：R in Formula II -1 and Formula II -21And R2Respectively benzyl, to Methyl benzenesulfonyl base (being abbreviated as TS)；Formula II -1 Corresponding product is designated as product 1-1, and the corresponding product of Formula II -1 is designated as product 1-2.
Product 1-1 Chinese is：N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitutions) two (N- benzyls Base -4- is to Methyl benzenesulfonyl base)；
Product 1-1 English name is：
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-benzyl-4- methy lbenzenesulfonamide)
Product 1-1 and 1-2 structural formula is respectively：
The connection enamine raw material used for：R in Formulas I1And R2Respectively benzyl and the connection enamine to Methyl benzenesulfonyl base.Specifically Preparation process is as follows：
In dry reaction tube, rhodium source, part, connection enamine, organic solvent are sequentially added, one is stirred under reaction temperature Section time, reaction terminate, and the water quenching for adding 1.5 times of organic solvent volume is gone out, and liquid separation retains organic layer.Organic layer is using organic molten After the saturated aqueous common salt that 2.5 times of agent volume washs 3 times respectively, anhydrous Na is used2SO4Dry, be evaporated under reduced pressure removing organic solvent, warp Column chromatography (solvent：Volume ratio ethyl acetate/petroleum ether=1/5) separation, gained solid is product 1.
Specifically the relation of raw material, proportioning, reaction condition, product yield and gained sample number into spectrum is as shown in table 1.
Table 1
Sample 1#- 1~sample 1#- 10 fusing point (mp)：135~137 DEG C.
Using thin-layer chromatography to sample 1#- 10 analyses：Rf=0.30 (ethyl acetate/petroleum ether=1/5, v/v).
Using nuclear magnetic resonance to sample 1#- 10 detections, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：7.59 (d, J=8.0Hz, 4H), 7.27 (d, J=6.0Hz, 14H), 5.16 (s, 2H), 4.82 (s, 2H), 4.59 (d, J=15.6Hz, 2H), 4.08 (s, 2H), 3.97 (d, J=15.6Hz, 2H),2.43(s,6H)。13C NMR(100MHz,CDCl3) chemical shift (ppm)：143.5,142.3,137.2,137.0, 129.7,128.6,127.7,127.3,108.0,62.3,48.7,21.6。
Using infrared spectrum to sample 1#- 10 detections (KBr), in following wave number (cm-1) there is diffraction maximum position：546,598, 660,698,740,771,813,1027.63,1090,1161,1344,1455,1494,1597,2924,3030。
Using high resolution mass spectrum HRMS (ESI+) to sample 1#- 10 analyses, it is as a result as follows：
With [C34H34N2O4S2+H]+Meter, calculated value：599.2035；Test data:599.2033.
Sample 1#- 1~sample 1#- 9 thin-layer chromatography, nuclear magnetic resonance, the analysis result of infrared spectrum and high resolution mass spectrum With sample 1#- 10 result is similar.Illustrate that technical scheme provided herein is capable of the preparation 1 of high selectivity high-purity, 2- dimethylene cyclobutane chipal compounds.
Using high-efficient liquid phase chromatogram HPLC to sample 1#- 7 analyses, it is as a result as follows：
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=70/30, v=1.0mL/ Min, λ=254nm, t (minor)=20.59min, t (major)=23.52min], ee=92%.
Using polarimeter to sample 1#- 7 analyses, it is as a result as follows：[α]D20=-8.6 (c=3.0, CHCl3).Sample 1#-8 ~sample 1#- 10 detection data and sample 1#- 7 is basically identical；When illustrating to use chiral ligand, products therefrom is mainly product 1-1.And sample 1#- 1~sample 1#- 6 basic does not have optical activity, and when illustrating to use achiral ligand, products therefrom is product 1- 1 and 1-2 mol ratios are 1:1 mixture, it is racemic product.
The preparation of the product 2 of embodiment 2
Product 2：R in Formula II -1 and Formula II -21And R2Respectively benzyl, methyl sulphonyl (being abbreviated as MS)；The correspondence of Formula II -1 Product is designated as product 2-1, and the corresponding product of Formula II -1 is designated as product 2-2.
Product 2-1 Chinese is：N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitutions) two (N- benzyls Base -4- methyl sulphonyls)
Product 2-1 English name is：
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-benzylmethane sulfonamide)
Product 2-1 and 2-2 structural formula is respectively：
Sample 1#-1 preparation, difference are in specific preparation process such as embodiment 1, the achirality and hand of use Property part is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)； The connection enamine raw material used for：R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute Obtain product and be designated as sample 2#- 1, yield 70%；Sample 2 is designated as using chiral ligand products therefrom#- 2, yield 60%.
Sample 2#- 1 and sample 2#- 2 fusing point (mp)：170~174 DEG C.
Using thin-layer chromatography to sample 2#- 1 and sample 2#- 2 analyses：Rf=0.5 (ethyl acetate/petroleum ether=1/5, v/ v)。
Using nuclear magnetic resonance to sample 2#- 1 and sample 2#- 2 detections, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：7.32 (s, 10H), 5.41 (s, 2H), 4.89 (d, J= 18.7Hz, 4H), 4.58 (d, J=15.5Hz, 2H), 4.14 (d, J=15.2Hz, 2H), 2.83 (s, 6H).13C NMR (100MHz,CDCl3) chemical shift (ppm)：142.7,137.2,128.8,128.5,128.0,107.9,61.7,48.9, 40.5。
Using infrared spectrum to sample 2#- 1 and sample 2#- 2 detections (KBr), in following wave number (cm-1) there is diffraction position Peak：518,699,757,792,961,1027,1150,1333,1456,1496,1681,2927,3030.32.
Using high resolution mass spectrum HRMS (ESI+) to sample 2#- 1 and sample 2#- 2 analyses, it is as a result as follows：
With [C22H26N2O4S2+H]+Meter, calculated value:447.1408；Test data:447.1407.
Using high-efficient liquid phase chromatogram HPLC to sample 2#- 2 analyses, it is as a result as follows：
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=70/30, v=1.0mL/ Min, λ=254nm, t (major)=10.93min, t (minor)=13.01min], ee=92%.
Using polarimeter to sample 2#- 2 analyses, it is as a result as follows：[α]D20=-24.6 (c=1.0, CHCl3).Sample 2#-1 For product 2-1 and product 2-2 racemic mixture；Sample 2#It is mainly product 2-1 in -2.
The preparation of the product 3 of embodiment 3
Product 3：R in Formula II -1 and Formula II -21And R2Respectively 4- methoxy-benzyls, Methyl benzenesulfonyl base (is abbreviated as TS)；The corresponding product of Formula II -1 is designated as product 3-1, and the corresponding product of Formula II -1 is designated as product 3-2.
Product 3-1 Chinese is：N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitutions) two (N- (4- methoxy-benzyls) -4- is to Methyl benzenesulfonyl base)
Product 3-1 English name is：
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-(4- methoxybenzyl)-4-methylbenzenesulfonamide)
Product 3-1 and product 3-2 structural formula is respectively：
Sample 1#-1 preparation, difference are in specific preparation process such as embodiment 1, the achirality and hand of use Property part is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)； The connection enamine raw material used for：R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute Obtain product and be designated as sample 3#- 1, yield 76%；Sample 3 is designated as using chiral ligand products therefrom#- 2, yield 79%.
Sample 3#- 1 and sample 3#- 2 fusing point (mp)：141~144 DEG C.
Using thin-layer chromatography to sample 3#- 1 and sample 3#- 2 analyses：Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/v)
Using nuclear magnetic resonance to sample 3#- 1 and sample 3#- 2 detections, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：7.58 (d, J=8.2Hz, 4H), 7.27 (d, J=8.0Hz, 4H), 7.19 (d, J=8.5Hz, 4H), 6.82 (d, J=8.6Hz, 4H), 5.16 (s, 2H), 4.78 (s, 2H), 4.54 (d, J= 15.2Hz, 2H), 4.06 (s, 2H), 3.92 (d, J=15.2Hz, 2H), 3.79 (s, 6H), 2.43 (s, 6H).13C NMR (100MHz,CDCl3) chemical shift (ppm)：159.2,143.4,142.4,137.3,130.1,129.7,128.9,127.3, 113.9,107.9,62.2,55.3,48.1,21.5。
Using infrared spectrum to sample 3#- 1 and sample 3#- 2 detections (KBr), in following wave number (cm-1) there is diffraction position Peak：535,663,751,814,881,915,1092,1164,1267,1315,1376,1455,1511,1612,2926.
Using high resolution mass spectrum HRMS (ESI+) to sample 3#- 1 and sample 3#- 2 analyses, it is as a result as follows：
With [C36H38N2O6S2+H]+Meter, calculated value:659.2248；Test data:659.2244.
Using high-efficient liquid phase chromatogram HPLC to sample 3#- 2 analyses, it is as a result as follows：
[Daicel Chiralpak IB (0.46cm x 25cm), n-hexane/isopropanol=90/10, v=1.0mL/ Min, λ=254nm, t (minor)=24.85min, t (major)=35.41min], ee=99%.
Using polarimeter to sample 3#- 2 analyses, it is as a result as follows：[α]D20=-19.8 (c=3.4, CHCl3).Sample 3#-1 For product 3-1 and product 3-2 racemic mixture；Sample 3#It is mainly product 3-1 in -2.
The preparation of the product 4 of embodiment 4
Product 4：R in Formula II -1 and Formula II -21And R2Respectively 1,3- benzos dioxy -5- methyl, to Methyl benzenesulfonyl base (being abbreviated as TS)；The corresponding product of Formula II -1 is designated as product 4-1, and the corresponding product of Formula II -1 is designated as product 4-2.
Product 4-1 Chinese is：N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitutions) two (N- (1,3- benzo dioxy -5- methyl) -4- is to Methyl benzenesulfonyl base)
Product 4-1 English name is：
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-(benzo[d][1, 3]dioxol-5-ylmethyl)-4-methylbenzenesulfonamide)
Product 4-1 and product 4-2 structural formula is respectively：
Sample 1#-1 preparation, difference are in specific preparation process such as embodiment 1, the achirality and hand of use Property part is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)； The connection enamine raw material used for：R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute Obtain product and be designated as sample 4#- 1, yield 86%；Sample 4 is designated as using chiral ligand products therefrom#- 2, yield 95%.
Sample 4#- 1 and sample 4#- 2 fusing point (mp)：68~71 DEG C.
Using thin-layer chromatography to sample 4#- 1 and sample 4#- 2 analyses：Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/ v)。
Using nuclear magnetic resonance to sample 4#- 1 and sample 4#- 2 detections, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：7.61 (d, J=8.2Hz, 4H), 7.29 (d, J=8.0Hz, 4H), 6.83 (s, 2H), 6.70-6.65 (m, 4H), 5.93 (s, 4H), 5.20 (s, 2H), 4.83 (s, 2H), 4.52 (d, J= 15.2Hz, 2H), 4.11 (s, 2H), 3.92 (d, J=15.3Hz, 2H), 2.43 (s, 6H).13C NMR(100MHz,CDCl3) change Displacement study (ppm)：148.0,147.3,143.5,142.2,137.3,130.7,129.7,127.3,121.9,109.3, 108.0,101.1,62.1,48.4,21.6。
Using infrared spectrum to sample 4#- 1 and sample 4#- 2 detections (KBr), in following wave number (cm-1) there is diffraction position Peak：547,661,811,928,1038,1090,1161,1243,1334,1446,1489,1503,1597,2922.
Using high resolution mass spectrum HRMS (ESI+) to sample 4#- 1 and sample 4#- 2 analyses, it is as a result as follows：
With [C36H34N2O8S2+H]+Meter, calculated value:687.1830；Test data:687.1829.
Using high-efficient liquid phase chromatogram HPLC to sample 4#- 2 analyses, it is as a result as follows：
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=70/30, v=1.0mL/ Min, λ=254nm, t (minor)=37.03min, t (major)=47.42min], ee=90%
Using polarimeter to sample 4#- 2 analyses, it is as a result as follows：[α]D20=-21.7 (c=4.5, CHCl3).Sample 4#-1 For product 4-1 and product 4-2 racemic mixture；Sample 4#It is mainly product 4-1 in -2.
The preparation of the product 5 of embodiment 5
Product 5：R in Formula II -1 and Formula II -21And R2Respectively 1- menaphthyls, to Methyl benzenesulfonyl base (being abbreviated as TS)；Formula II-1 corresponding products are designated as product 5-1, and the corresponding product of Formula II -1 is designated as product 5-2.
Product 5-1 Chinese is：N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitutions) two (N- (1- menaphthyls) -4- is to Methyl benzenesulfonyl base)
Product 5-1 English name is：
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(4-methyl-N- (naphthalen-1-ylmethyl)benzenesulfonamide)
Product 5-1 and product 5-2 structural formula is respectively：
Sample 1#-1 preparation, difference are in specific preparation process such as embodiment 1, the achirality and hand of use Property part is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)； The connection enamine raw material used for：R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute Obtain product and be designated as sample 5#- 1, yield 71%；Sample 5 is designated as using chiral ligand products therefrom#- 2, yield 84%.
Sample 5#- 1 and sample 5#- 2 fusing point (mp)：130~134 DEG C.
Using thin-layer chromatography to sample 5#- 1 and sample 5#- 2 analyses：Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/ v)。
Using nuclear magnetic resonance to sample 5#- 1 and sample 5#- 2 detections, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：8.17 (d, J=8.1Hz, 2H), 7.84 (d, J=7.5Hz, 2H), 7.78 (d, J=8.0Hz, 2H), 7.52-7.45 (m, 4H), 7.38-7.25 (m, 8H), 7.17 (d, J=8.0Hz, 4H), 5.11 (t, J=9.2Hz, 4H), 4.57 (s, 2H), 4.36 (d, J=15.4Hz, 2H), 3.77 (s, 2H), 2.39 (s, 6H).13C NMR(100MHz,CDCl3) chemical shift (ppm)：143.4,142.3,136.7,133.7,131.5,131.5,129.6, 128.6,128.5,127.8,127.3,126.4,125.8,125.4,123.6,107.9,62.6,46.7,21.5。
Using infrared spectrum to sample 5#- 1 and sample 5#- 2 detections (KBr), in following wave number (cm-1) there is diffraction position Peak：547,666,791,889,1037,1091,1161,1337,1510,1597,2922,3296.
Using high resolution mass spectrum HRMS (ESI+) to sample 5#- 1 and sample 5#- 2 analyses, it is as a result as follows：
With [C42H38N2O4S2+H]+Meter, calculated value:699.2350；Test data:699.2346.
Using high-efficient liquid phase chromatogram HPLC to sample 5#- 2 analyses, it is as a result as follows：
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=70/30, v=1.0mL/ Min, λ=254nm, t (major)=19.07min, t (minor)=32.05min], ee=78%
Using polarimeter to sample 5#- 2 analyses, it is as a result as follows：[α]D20=-28.2 (c=3.7, CHCl3).Sample 5#-1 For product 5-1 and product 5-2 racemic mixture；Sample 5#It is mainly product 5-1 in -2.
The preparation of the product 6 of embodiment 6
Product 6：R in Formula II -1 and Formula II -21And R2Respectively phenethyl, to Methyl benzenesulfonyl base (being abbreviated as TS)；Formula II-1 corresponding products are designated as product 6-1, and the corresponding product of Formula II -1 is designated as product 6-2.
Product 6-1 Chinese is：N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitutions) two (N- benzene Ethyl -4- is to Methyl benzenesulfonyl base)
Product 6-1 English name is：
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(4-methyl-N- phenethylbenzenesulfonamide)
Product 6-1 and product 6-2 structural formula is respectively：
Sample 1#-1 preparation, difference are in specific preparation process such as embodiment 1, the achirality and hand of use Property part is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)； The connection enamine raw material used for：R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute Obtain product and be designated as sample 6#- 1, yield 89%；Sample 6 is designated as using chiral ligand products therefrom#- 2, yield 58%.
Sample 6#- 1 and sample 6#- 2 fusing point (mp)：137~141 DEG C.
Using thin-layer chromatography to sample 6#- 1 and sample 6#- 2 analyses：Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/ v)。
Using nuclear magnetic resonance to sample 6#- 1 and sample 6#- 2 detections, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：7.84 (d, J=8.2Hz, 4H), 7.33 (t, J=7.5Hz, 8H), 7.26 (dd, J=13.2,8.8Hz, 6H), 5.21 (s, 2H), 5.13 (s, 2H), 4.32 (s, 2H), 3.49-3.41 (m, 2H),3.16-3.05(m,4H),3.01-2.92(m,2H),2.40(s,6H)。13C NMR(100MHz,CDCl3) chemical shift (ppm)：143.9,142.7,138.7,137.0,129.9,128.8,128.6,127.4,126.6,108.1,61.7,46.4, 37.6,21.5。
Using infrared spectrum to sample 6#- 1 and sample 6#- 2 detections (KBr), in following wave number (cm-1) there is diffraction position Peak：
502,574,668,750,838,910,987,1040,1236,1309,1454,1597,2924,3029。
Using high resolution mass spectrum HRMS (ESI+) to sample 6#- 1 and sample 6#- 2 analyses, it is as a result as follows：
With [C36H38N2O4S2+H]+Meter, calculated value:627.2346；Test data:627.2346.
Using high-efficient liquid phase chromatogram HPLC to sample 6#- 2 analyses, it is as a result as follows：
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=95/5, v=1.0mL/min, λ=254nm, t (major)=28.70min, t (minor)=40.80min], ee=99%.
Using polarimeter to sample 6#- 2 analyses, it is as a result as follows：[α]D20=-139.9 (c=0.7, CHCl3).Sample 6#- 1 is product 6-1 and product 6-2 racemic mixture；Sample 6#It is mainly product 6-1 in -2.
The preparation of the product 7 of embodiment 7
Product 7：R in Formula II -1 and Formula II -21And R2Respectively 3,3- diphenyl propyls, Methyl benzenesulfonyl base (is abbreviated as TS)；The corresponding product of Formula II -1 is designated as product 7-1, and the corresponding product of Formula II -1 is designated as product 7-2.
Product 7-1 Chinese is：N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitutions) two (N- (3,3- diphenyl propyls) -4- is to Methyl benzenesulfonyl base)
Product 7-1 English name is：
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-(3,3- diphenylpropyl)-4-methylbenzenesulfonamide)
Product 7-1 and product 7-2 structural formula is respectively：
Sample 1#-1 preparation, difference are in specific preparation process such as embodiment 1, the achirality and hand of use Property part is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)； The connection enamine raw material used for：R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute Obtain product and be designated as sample 7#- 1, yield 63%；Sample 7 is designated as using chiral ligand products therefrom#- 2, yield 71%.
Sample 7#- 1 and sample 7#- 2 fusing point (mp)：169~170 DEG C.
Using thin-layer chromatography to sample 7#- 1 and sample 7#- 2 analyses：Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/ v)。
Using nuclear magnetic resonance to sample 7#- 1 and sample 7#- 2 detections, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：7.60 (d, J=8.1Hz, 4H), 7.28-7.17 (m, 24H), 5.07 (s, H), 4.87 (s, 2H), 4.21 (s, 2H), 3.80 (t, J=8.0Hz, 2H), 3.15-3.07 (m, 2H), 2.85-2.77(m,2H),2.57-2.43(m,4H),2.36(s,6H)。13C NMR(100MHz,CDCl3) chemical shift (ppm)： 144.0,143.9,143.5,142.6,136.8,129.8,128.6,127.9,127.8,127.3,126.3,107.9,61.7, 49.3,43.7,36.3,21.5。
Using infrared spectrum to sample 7#- 1 and sample 7#- 2 detections (KBr), in following wave number (cm-1) there is diffraction position Peak：546,585,664,764,814,909,1061,1092,1161,1208,1345,1451,1493,1598,2925,3026.
Using high resolution mass spectrum HRMS (ESI+) to sample 7#- 1 and sample 7#- 2 analyses, it is as a result as follows：
With [C50H50N2O4S2+H]+Meter, calculated value:807.3292；Test data:807.3285.
Using high-efficient liquid phase chromatogram HPLC to sample 7#- 2 analyses, it is as a result as follows：
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=70/30, v=1.0mL/ Min, λ=254nm, t (minor)=11.65min, t (major)=14.71min], ee=97%.
Using polarimeter to sample 7#- 2 analyses, it is as a result as follows：[α]D20=-17.7 (c=5.6, CHCl3).Sample 7#-1 For product 7-1 and product 7-2 racemic mixture；Sample 7#It is mainly product 7-1 in -2.
The preparation of the product 8 of embodiment 8
Product 8：R in Formula II -1 and Formula II -21And R2Respectively 3- indolylethyls, to Methyl benzenesulfonyl base (being abbreviated as TS)； The corresponding product of Formula II -1 is designated as product 8-1, and the corresponding product of Formula II -1 is designated as product 8-2.
Product 8-1 Chinese is：N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitutions) two (N- (3- indolylethyls) -4- is to Methyl benzenesulfonyl base)
Product 8-1 English name is：
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-(2-(1H-indol- 3-yl)ethyl)-4-methylbenzenesulfonamide)
Product 8-1 and product 8-2 structural formula is respectively：
Sample 1#-1 preparation, difference are in specific preparation process such as embodiment 1, the achirality and hand of use Property part is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)； The connection enamine raw material used for：R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute Obtain product and be designated as sample 8#- 1, yield 88%；Sample 8 is designated as using chiral ligand products therefrom#- 2, yield 86%.
Sample 8#- 1 and sample 8#- 2 fusing point (mp)：185~188 DEG C.
Using thin-layer chromatography to sample 8#- 1 and sample 8#- 2 analyses：Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/ v)。
Using nuclear magnetic resonance to sample 8#- 1 and sample 8#- 2 detections, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：8.06 (s, 2H), 7.85 (d, J=8.2Hz, 4H), 7.72 (d, J=7.7Hz, 2H), 7.36 (d, J=7.9Hz, 2H), 7.29 (d, J=8.1Hz, 4H), 7.21-7.13 (m, 4H), 7.05 (s,2H),5.20(s,4H),4.30(s,2H),3.62-3.54(m,2H),3.29-3.11(m,6H),2.37(s,6H)。13C NMR(100MHz,CDCl3) chemical shift (ppm)：143.8,142.9,137.2,136.3,129.9,127.4,127.3, 122.2,122.1,119.5,119.0,112.9,111.2,108.1,62.1,45.8,27.4,21.5。
Using infrared spectrum to sample 8#- 1 and sample 8#- 2 detections (KBr), in following wave number (cm-1) there is diffraction position Peak：424,546,661,751,815,906,988,1012,1088,1159,1205,1257,1337,1457,1596,2852, 3402。
Using high resolution mass spectrum HRMS (ESI+) to sample 8#- 1 and sample 8#- 2 analyses, it is as a result as follows：
With [C40H40N4O4S2+H]+Meter, calculated value:705.2564；Test data:705.2566.
Using high-efficient liquid phase chromatogram HPLC to sample 8#- 2 analyses, it is as a result as follows：
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=70/30, v=1.0mL/ Min, λ=254nm, t (major)=12.70min, t (minor)=22.11min], ee=74%
Using polarimeter to sample 8#- 2 analyses, it is as a result as follows：[α]D20=-88.1 (c=1.0, CHCl3).Sample 8#-1 For product 8-1 and product 8-2 racemic mixture；Sample 8#It is mainly product 8-1 in -2.
The preparation of the product 9 of embodiment 9
Product 9：R in Formula II -1 and Formula II -21And R2Respectively 2- thienylethyls, to Methyl benzenesulfonyl base (being abbreviated as TS)； The corresponding product of Formula II -1 is designated as product 9-1, and the corresponding product of Formula II -1 is designated as product 9-2.
Product 9-1 Chinese is：N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitutions) two (N- (2- thienylethyls) -4- is to Methyl benzenesulfonyl base)
Product 9-1 English name is：
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(4-methyl-N-(2- (thiophen-2-yl)ethyl)benzenesulfonamide)
Product 9-1 and product 9-2 structural formula is respectively：
Sample 1#-1 preparation, difference are in specific preparation process such as embodiment 1, the achirality and hand of use Property part is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)； The connection enamine raw material used for：R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute Obtain product and be designated as sample 9#- 1, yield 65%；Sample 9 is designated as using chiral ligand products therefrom#- 2, yield 67%.
Sample 9#- 1 and sample 9#- 2 fusing point (mp)：191~195 DEG C.
Using thin-layer chromatography to sample 9#- 1 and sample 9#- 2 analyses：Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/ v)。
Using nuclear magnetic resonance to sample 9#- 1 and sample 9#- 2 detections, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：7.82 (d, J=8.4Hz, 4H), 7.34 (d, J=8.4Hz, 4H), 7.16 (d, J=4.3Hz, 2H), 6.96 (dd, J=5.2,3.6Hz, 2H), 6.88 (d, J=2.8Hz, 2H), 5.20 (s, 2H),5.01(s,2H),4.27(s,2H),3.56-3.48(m,2H),3.35-3.27(m,2H),3.20-3.10(m,4H), 2.42(s,6H)。13C NMR(100MHz,CDCl3) chemical shift (ppm)：143.9,142.5,140.7,136.8,130.0, 127.4,127.0,125.4,123.8,108.2,61.8,46.3,31.6,21.6。
Using infrared spectrum to sample 9#- 1 and sample 9#- 2 detections (KBr), in following wave number (cm-1) there is diffraction position Peak：499,545,585,666,700,766,851,894,987,1053,1108,1229,1308,1344,1489,1596, 2937。
Using high resolution mass spectrum HRMS (ESI+) to sample 9#- 1 and sample 9#- 2 analyses, it is as a result as follows：
With [C32H34N2O4S4+H]+Meter, calculated value:639.1477；Test data:639.1474.
Using high-efficient liquid phase chromatogram HPLC to sample 9#- 2 analyses, it is as a result as follows：
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=99/1, v=1.0mL/min, λ=254nm, t (major)=39.80min, t (minor)=47.92min], ee=99%
Using polarimeter to sample 9#- 2 analyses, it is as a result as follows：[α]D20=-29.3 (c=3.0, CHCl3).Sample 9#-1 For product 9-1 and product 9-2 racemic mixture；Sample 9#It is mainly product 9-1 in -2.
The preparation of the product 10 of embodiment 10
Product 10：R in Formula II -1 and Formula II -21And R2Respectively 2- furfuryls, Methyl benzenesulfonyl base (is abbreviated as TS)；The corresponding product of Formula II -1 is designated as product 10-1, and the corresponding product of Formula II -1 is designated as product 10-2.
Product 10-1 Chinese is：N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitutions) two (N- (2- furfuryls) -4- is to Methyl benzenesulfonyl base)
Product 10-1 English name is：
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(4-methyl-N- ((tetrahydrofuran-2-yl)methyl)benzenesulfonamide)
Product 10-1 and product 10-2 structural formula is respectively：
Sample 1#-1 preparation, difference are in specific preparation process such as embodiment 1, the achirality and hand of use Property part is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)； The connection enamine raw material used for：R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute Obtain product and be designated as sample 10#- 1, yield 71%；Sample 10 is designated as using chiral ligand products therefrom#- 2, yield 79%.
Sample 10#- 1 and sample 10#- 2 fusing point (mp)：72~75 DEG C.
Using thin-layer chromatography to sample 10#- 1 and sample 10#- 2 analyses：Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/ v)。
Using nuclear magnetic resonance to sample 10#- 1 and sample 10#- 2 detections, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：7.87-7.75 (m, 4H), 7.31 (d, J=7.3Hz, 4H), 5.47-5.19(m,4H),4.67(s,1H),4.24(s,1H),4.13-4.01(m,2H),3.90-3.80(m,2H),3.74- 3.64(m,2H),3.47-3.35(m,2H),3.30-3.22(m,2H),2.42(s,6H),2.01-1.78(m,6H),1.76- 1.70(m,1H),1.61-1.44(m,1H)。
13C NMR(100MHz,CDCl3) chemical shift (ppm)：144.3,143.6,143.3,143.2,143.1, 142.6,137.5,137.3,137.2,129.8,129.7,129.6,127.6,127.4,127.3,107.5,107.4,78.8, 78.7,77.9,67.9,67.8,62.5,62.4,61.4,49.3,49.0,29.5,29.1,25.4,25.3,21.5。
Using infrared spectrum to sample 10#- 1 and sample 10#- 2 detections (KBr), in following wave number (cm-1) there is diffraction position Peak：547,660,706 766,815,1032,1089,1163,1346,1447,1494,1598,2871,2924.
Using high resolution mass spectrum HRMS (ESI+) to sample 10#- 1 and sample 10#- 2 analyses, it is as a result as follows：With [C30H38N2O6S2+H]+Meter, calculated value:587.2245；Test data:587.2244.
Using high-efficient liquid phase chromatogram HPLC to sample 10#- 2 analyses, it is as a result as follows：
[Daicel Chiralpak IF (0.46cm x 25cm), n-hexane/isopropanol=90/10, v=1.0mL/ Min, λ=254nm, t (major)=59.68min, t (minor)=72.86min], ee=90%
Using polarimeter to sample 10#- 2 analyses, it is as a result as follows：[α]D20=-14.4 (c=3.0, CHCl3).Sample 10#- 1 is product 10-1 and product 10-2 racemic mixture；Sample 10#It is mainly product 10-1 in -2.
The preparation of the product 11 of embodiment 11
Product 11：R in Formula II -1 and Formula II -21And R2Respectively normal-butyl, to Methyl benzenesulfonyl base (being abbreviated as TS)；Formula II-1 corresponding products are designated as product 11-1, and the corresponding product of Formula II -1 is designated as product 11-2.
Product 11-1 Chinese is：N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitutions) two (N- Butyl -4- is to Methyl benzenesulfonyl base)
Product 11-1 English name is：
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-butyl-4- methyl benzenesulfonamide)
Product 11-1 and product 11-2 structural formula is respectively：
Sample 1#-1 preparation, difference are in specific preparation process such as embodiment 1, the achirality and hand of use Property part is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)； The connection enamine raw material used for：R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute Obtain product and be designated as sample 11#- 1, yield 66%；Sample 11 is designated as using chiral ligand products therefrom#- 2, yield 67%.
Sample 11#- 1 and sample 11#- 2 fusing point (mp)：108~112 DEG C.
Using thin-layer chromatography to sample 11#- 1 and sample 11#- 2 analyses：Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/ v)。
Using nuclear magnetic resonance to sample 11#- 1 and sample 11#- 2 detections, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：7.78 (d, J=8.0Hz, 4H), 7.33 (d, J=8.0Hz, 4H),5.25(s,2H),5.01(s,2H),4.43(s,2H),3.25-3.17(m,2H),2.99-2.91(m,2H),2.43(s, 6H), 1.70-1.49 (m, 4H), 1.29-1.20 (m, 4H), 0.88 (t, J=7.3Hz, 6H).
13C NMR(100MHz,CDCl3) chemical shift (ppm)：143.5,143.1,137.3,129.8,127.4, 107.8,61.6,44.8,32.9,21.5,20.2,13.6。
Using infrared spectrum to sample 11#- 1 and sample 11#- 2 detections (KBr), in following wave number (cm-1) there is diffraction position Peak：544,568,664,731,765,813,898,999,1029,1090,1139,1165,1221,1250,1345,2954.
Using high resolution mass spectrum HRMS (ESI+) to sample 11#- 1 and sample 11#- 2 analyses, it is as a result as follows：With [C28H38N2O4S2+H]+Meter, calculated value:531.2343；Test data:531.2346.
Using high-efficient liquid phase chromatogram HPLC to sample 11#- 2 analyses, it is as a result as follows：
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=90/10, v=1.0mL/ Min, λ=254nm, t (minor)=19.29min, t (major)=26.54min], ee=82%
Using polarimeter to sample 11#- 2 analyses, it is as a result as follows：[α]D20=-21.5 (c=4.2, CHCl3).Sample 11#- 1 is product 11-1 and product 11-2 racemic mixture；Sample 11#It is mainly product 11-1 in -2.
The preparation of the product 12 of embodiment 12
Product 12：R in Formula II -1 and Formula II -21And R2Respectively tert-butyl dimethyl silica ethyl (the tert-butyl group two therein Methyl siloxy is abbreviated as OTBS), to Methyl benzenesulfonyl base (being abbreviated as TS)；The corresponding product of Formula II -1 is designated as product 12-1, formula II-1 corresponding products are designated as product 12-2.
Product 12-1 Chinese is：N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitutions) two (N- Tert-butyl dimethyl silica ethyl -4- is to Methyl benzenesulfonyl base)
Product 12-1 English name is：
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-(2-((tert- butyldimethylsilyl)oxy)ethyl)-4-methylbenzenesulfonamide)
Product 12-1 and product 12-2 structural formula is respectively：
Sample 1#-1 preparation, difference are in specific preparation process such as embodiment 1, the achirality and hand of use Property part is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)； The connection enamine raw material used for：R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute Obtain product and be designated as sample 12#- 1, yield 84%；Sample 12 is designated as using chiral ligand products therefrom#- 2, yield 93%.
Sample 12#- 1 and sample 12#- 2 fusing point (mp)：126~128 DEG C.
Using thin-layer chromatography to sample 12#- 1 and sample 12#- 2 analyses：Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/ v)。
Using nuclear magnetic resonance to sample 12#- 1 and sample 12#- 2 detections, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：7.69 (d, J=8.0Hz, 4H), 7.25 (d, J=8.0Hz, 4H),5.12(s,2H),4.89(s,2H),4.11(s,2H),3.82-3.70(m,4H),3.25-3.17(m,2H),2.99- 2.92(m,2H),2.35(s,6H),0.81(s,18H),-0.00(s,12H)。13C NMR(100MHz,CDCl3) chemical shift (ppm)：143.7,142.6,136.9,129.8,127.3,108.0,62.7,62.2,46.0,25.9,21.5,18.3,-5.3.
Using infrared spectrum to sample 12#- 1 and sample 12#- 2 detections (KBr), in following wave number (cm-1) there is diffraction position Peak：548,664,777,837,1089,1163,1255,1345,1471,1597,2929.
Using high resolution mass spectrum HRMS (ESI+) to sample 12#- 1 and sample 12#- 2 analyses, it is as a result as follows：With [C36H58N2O6S2Si2+H]+Meter, calculated value:735.3351；Test data:735.3348.
Using high-efficient liquid phase chromatogram HPLC to sample 12#- 2 analyses, it is as a result as follows：
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=99/1, v=1.0mL/min, λ=254nm, t (minor)=23.67min, t (major)=33.71min], ee=96%
Using polarimeter to sample 12#- 2 analyses, it is as a result as follows：[α]D20=-9.3 (c=7.8, CHCl3).Sample 12#- 1 is product 12-1 and product 12-2 racemic mixture；Sample 12#It is mainly product 12-1 in -2.
The preparation of the product 13 of embodiment 13
Product 13：R in Formula II -1 and Formula II -21And R2Respectively 9- octadecylenes base, Methyl benzenesulfonyl base (is abbreviated as TS)；The corresponding product of Formula II -1 is designated as product 13-1, and the corresponding product of Formula II -1 is designated as product 13-2.
Product 13-1 Chinese is：N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitutions) two (N- (9- octadecylenes base) -4- is to Methyl benzenesulfonyl base)
Product 13-1 English name is：
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(4-methyl-N- ((Z)-octadec-9-en-1-yl)benzenesulfonamide)
Product 13-1 and product 13-2 structural formula is respectively：
Sample 1#-1 preparation, difference are in specific preparation process such as embodiment 1, the achirality and hand of use Property part is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)； The connection enamine raw material used for：R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute Obtain product and be designated as sample 13#- 1, yield 76%；Sample 13 is designated as using chiral ligand products therefrom#- 2, colorless oil, yield is 50%.
Using thin-layer chromatography to sample 13#- 1 and sample 13#- 2 analyses：Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/ v)。
Using nuclear magnetic resonance to sample 13#- 1 and sample 13#- 2 detections, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：7.70 (d, J=8.0Hz, 4H), 7.25 (d, J=7.6Hz, 4H), 5.31 (d, J=14.6Hz, 4H), 5.18 (s, 2H), 4.94 (s, 2H), 4.36 (s, 2H), 3.16-3.09 (m, 2H), 2.91-2.83(m,2H),2.35(s,6H),1.94-1.89(m,8H),1.64-1.46(m,4H),1.18(s,44H),0.80 (d, J=6.8Hz, 6H).13C NMR(100MHz,CDCl3) chemical shift (ppm)：143.5,143.2,137.3,129.9, 129.8,129.7,127.6,107.8,61.6,45.1,32.6,31.9,30.9,29.8,29.7,29.5,29.3,29.2, 29.1,27.2,27.0,22.7,21.5,17.1。
Using infrared spectrum to sample 13#- 1 and sample 13#- 2 detections (KBr), in following wave number (cm-1) there is diffraction position Peak：546,565,661,722,813,895,1090,1160,1346,1465,1598,2854,2925.
Using high resolution mass spectrum HRMS (ESI+) to sample 13#- 1 and sample 13#- 2 analyses, it is as a result as follows：With [C56H90N2O4S2+H]+Meter, calculated value:919.6415；Test data:919.6421.
Using high-efficient liquid phase chromatogram HPLC to sample 13#- 2 analyses, it is as a result as follows：
[Daicel Chiralpak ID (0.46cm x 25cm), n-hexane/isopropanol=99/1, v=1.0mL/min, λ=254nm, t (major)=43.84min, t (minor)=65.22min], ee=84%
Using polarimeter to sample 13#- 2 analyses, it is as a result as follows：[α]D20=-13.7 (c=5.2, CHCl3).Sample 13#- 1 is product 13-1 and product 13-2 racemic mixture；Sample 13#It is mainly product 13-1 in -2.
Embodiment 14
The cycloaddition reaction of gained 1,2- dimethylene cyclobutane chipal compounds and dimethyl maleate：
Sample 1 is sequentially added in the reaction tube that one dries#- 7 (120mg, 0.2mmol), dimethyl maleate (170.5mg, 1.2mmol) and toluene (20mL), react 7 hours, be quenched with water at 110 DEG C, then with water (50mL) and dichloro Methane (50mL) is extracted, stratification, and organic phase is collected, and aqueous phase is extracted (3 × 50mL) with dichloromethane.Merge organic layer, do It is dry, concentration, column chromatography purifying (silica gel petrol ether/ethyl acetate:2/1) product (145.2mg, with sample 1, that is, is obtained#- 1 rubs That number meter, 98%) yield of product is.
Product is detected using nuclear magnetic resonance, it is as a result as follows：
1H NMR(400MHz,CDCl3) chemical shift (ppm)：7.63 (d, J=8.0Hz, 4H), 7.31 (d, J=8.0Hz, 4H), 7.25 (t, J=3.0Hz, 6H), 7.16 (t, J=2.6Hz, 4H), 5.18 (s, 2H), 4.24 (s, 4H), 3.71 (s, 6H), 2.91(s,4H),2.47(s,6H)。13C NMR(100MHz,CDCl3) chemical shift (ppm)：167.1,143.9,137.5, 135.0,134.8,131.8,129.7,128.6,128.5,128.0,127.4,121.5,54.6,52.2,28.9,21.6。
Using infrared spectrum to sample 14#Detect (KBr), in following wave number (cm-1) there is diffraction maximum position：549,643, 738,777,952,1091,1162,1307,1345,1453,1598,1650,1733,2919,2950,3034,3060。
Using high resolution mass spectrum HRMS (ESI+) to sample 14#Analysis, it is as a result as follows：
With [C40H40N2O8S2+H]+Meter, calculated value:741.2299；Test data:741.2300.
It is described above, only it is several embodiments of the application, any type of limitation is not done to the application, although this Shen Please with preferred embodiment disclose as above, but and be not used to limit the application, any person skilled in the art, do not taking off In the range of technical scheme, make a little variation using the technology contents of the disclosure above or modification is equal to Case study on implementation is imitated, is belonged in the range of technical scheme.

Claims (10)

1. the method for one kind synthesis 1,2- dimethylene cyclobutane chipal compounds, it is characterised in that in the presence of rhodium complex Under, 1,2- dimethylene cyclobutane chipal compounds are synthesized by connection enamine compound；
The rhodium complex is formed by the rhodium source containing rhodium element with part；The part is that chiral ligand and/or achirality are matched somebody with somebody Body；The chiral ligand and achiral ligand are selected from least one in the organic compound containing P elements and/or nitrogen Kind；
The enamine compound, which is selected from, has at least one of compound of chemical structural formula shown in Formulas I：
The 1,2- dimethylenes cyclobutane chipal compounds be have as shown in Formula II -1 compound of chemical structural formula and/or Compound with the chemical structural formula as shown in Formula II -2：
In Formulas I, Formula II -1 and Formula II -2, R1、R2Independently selected from the aliphatic group of hydrogen, carbon number no more than 18, there is formula The group of structural formula shown in III, the group with structural formula shown in Formula IV, the group with structural formula shown in Formula V, with Formula IV The group of shown structural formula or the group with structural formula shown in Formula VII：
In formula III, R3Selected from aliphatic group of the carbon number no more than 18, substituted fatty hydrocarbon base of the carbon number no more than 18, virtue Base, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroarylalkyl, substitution heteroarylalkyl；
R4- A- formula IVs
In formula IV, A is selected from the alkylene that carbon number is no more than 10；R4It is former selected from aliphatic group of the carbon number no more than 18, carbon Subnumber no more than 18 substituted fatty hydrocarbon base, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, Heteroarylalkyl, substitution heteroarylalkyl, silylation；
R5- O-B- Formula V
In Formula V, B is selected from the alkylene no more than 10 from carbon number；R5Selected from aliphatic group of the carbon number no more than 18, carbon Substituted fatty hydrocarbon base of the atomicity no more than 18, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substitution aralkyl Base, heteroarylalkyl, substitution heteroarylalkyl, silylation；
In Formula IV, R6Selected from aliphatic group of the carbon number no more than 18, substituted fatty hydrocarbon base of the carbon number no more than 18, virtue Base, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroarylalkyl, substitution heteroarylalkyl, silylation；
In Formula VII, R7Selected from aliphatic group of the carbon number no more than 18, substituted fatty hydrocarbon base of the carbon number no more than 18, virtue Base, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroarylalkyl, substitution heteroarylalkyl, silylation.
2. according to the method for claim 1, it is characterised in that in Formulas I and Formula II, R1、R2Independently selected from carbon number not Aliphatic group, acetyl group, benzyl, 4- methoxy-benzyls, 1- menaphthyls, tert-butyl dimethyl silica ethyl, 3,3- more than 18 Diphenyl propyl, 2- phenethyls, furfuryl, thienylethyl, indolylethyl, 1,3- benzo dioxy -5- methyl, tertiary butyloxycarbonyl Base, benzoyl, tablet held before the breast by officials methoxycarbonyl group, tri-chloroethoxy base formoxyl, p-nitrophenyl sulfonyl, to Methyl benzenesulfonyl base or methyl sulphur Acyl group；Preferably, R1And R2In it is at least one be selected from structural formula shown in formula III group.
3. according to the method for claim 1, it is characterised in that the rhodium source is selected from dimerization rhodium acetate, triphenylphosphine chlorination Rhodium carbonyl, dimerization hydroxyl (1,5- cyclo-octadiene) rhodium (I), praseodynium rhodium (III), the rhodium of four carbonyl dichloride two, (1,5- Cyclo-octadiene) chlorine rhodium (I) dimer, the rhodium of dichloride two (double down borneol diene), acetylacetone,2,4-pentanedione bi-vinyl rhodium, acetylacetone,2,4-pentanedione (1,5- cyclo-octadiene) rhodium, trifluoroacetic acid rhodium (II) dimer, four or three [- (+)-N- (to dodecyl benzene sulfonyl) porphyrins] two Rhodium, dichloro (pentamethylcyclopentadiene base) close at least one of rhodium dimer, triphenylphosphine hydrogenized carbonyl rhodium.
4. according to the method for claim 1, it is characterised in that the part is achiral ligand, selected from formula (1) institute Show the compound of structural formula, the compound of structural formula shown in formula (2), the compound of structural formula shown in formula (3), tie shown in formula (4) At least one of the compound of structural formula shown in the compound of structure formula, formula (5), compound of structural formula shown in formula (6)：
In formula (1), R8Selected from hydrogen ,-CH3、—OCH3、—N(CH3)2、—OCH(CH3)2；R9Selected from hydrogen ,-OCH3、—N (CH3)2、—OCH(CH3)2；R10Selected from cyclohexyl ,-C (CH3)3；
In formula (2), R11Selected from-OCH2CH3、—C(CH3)3, phenyl；
In formula (3), R12Selected from phenyl, cyclohexyl；N is 1 or 3；
In formula (4), R13Selected from phenyl ,-C (CH3)3；
In formula (5), R14Selected from hydrogen, phenyl ,-CH3；R15Selected from hydrogen ,-CH3、—C(CH3)3；
In formula (6), R16Selected from-CH3Or-COOH.
5. according to the method for claim 1, it is characterised in that the part is chiral ligand, selected from formula (7) Suo Shi The compound of structural formula shown in the compound of structural formula, formula (8), the compound of structural formula shown in formula (9), structure shown in formula (10) The compound of structural formula shown in the compound of formula, formula (11), the compound of structural formula shown in formula (12), structural formula shown in formula (13) Compound, the compound of structural formula shown in formula (14), the compound of structural formula shown in formula (15), structural formula shown in formula (16) The change of the compound of structural formula shown in compound, formula (17), the compound of structural formula shown in formula (18), structural formula shown in formula (19) At least one of compound of structural formula shown in compound, formula (20)：
In formula (7), R17Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- bis- Aminomethyl phenyl, p-nitrophenyl；R18Selected from methyl, phenyl, the tert-butyl group, isopropyl, cyclohexyl；
In formula (8), R19Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- bis- Aminomethyl phenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (9), R20Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- bis- Aminomethyl phenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (10), R21Selected from methyl, phenyl, trifluoromethy phenyl；R22Selected from methyl, phenyl, trifluoromethy phenyl, first Phenyl, 2,4,6- trimethylphenyls, 3,5- 3,5-dimethylphenyls, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (11), R23Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (12), R24Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (13), R25Selected from H, F；R26Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethyls Phenyl, 3,5- 3,5-dimethylphenyls, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (18), R27Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (19), R28Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (20), R29Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl.
6. according to the method for claim 1, it is characterised in that including at least following steps：
A) rhodium source, chirality and/or achiral ligand, connection enamine compound are added in organic solvent, at -78 DEG C to 120 DEG C Stirring reaction 10 minutes to 120 hours；
B) after reaction terminates, add water quenching to go out, through liquid separation, washing, drying, removing organic solvent, separation, it is sub- to produce 1, the 2- bis- Methyl cyclobutane chipal compounds.
7. according to the method for claim 5, it is characterised in that reaction temperature is -20 DEG C to 100 DEG C in step a)；Reaction Time is 10 minutes to 48 hours.
8. according to the method for claim 5, it is characterised in that connection enamine compound and rhodium source and part rubs in step a) You are at ratio：
Join enamine compound：Rh：Part=1：0.01~1：0.01~1；
Preferably, connection enamine compound and the molar ratio in rhodium source and part are in step a)：
Join enamine compound：Rh：Part=1：0.01~0.15：0.05~0.50；
The molal quantity in the rhodium source is in terms of the molal quantity of rhodium element contained in rhodium source.
9. according to the method for claim 5, it is characterised in that organic solvent described in step a) be selected from benzene, carbon tetrachloride, Petroleum ether, tetrahydrofuran, dimethylformamide, acetone, ether, dichloromethane, chloroform, toluene, dimethylbenzene, chlorobenzene, neighbour At least one of dichloro-benzenes, hexamethylene, n-hexane, normal heptane, the ring of dioxane six, acetonitrile, methanol, ethanol, pentane.
10. according to the method for claim 5, it is characterised in that the method for the step b) separation is selected from recrystallization, thin layer At least one of chromatography, column chromatography, vacuum distillation；
In the recrystallization, thin-layer chromatography and column chromatography method, used solvent is the mixed of polar solvent and non-polar solven Compound；Wherein, the volume ratio of polar solvent and non-polar solven is 1：0.1~500.
CN201610335358.9A 2016-05-19 2016-05-19 A method of synthesis 1,2- dimethylene cyclobutane chipal compounds Active CN107400036B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201610335358.9A CN107400036B (en) 2016-05-19 2016-05-19 A method of synthesis 1,2- dimethylene cyclobutane chipal compounds
PCT/CN2016/085058 WO2017197670A1 (en) 2016-05-19 2016-06-07 Method for synthesizing 1,2-dimethylene cyclobutane chiral compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610335358.9A CN107400036B (en) 2016-05-19 2016-05-19 A method of synthesis 1,2- dimethylene cyclobutane chipal compounds

Publications (2)

Publication Number Publication Date
CN107400036A true CN107400036A (en) 2017-11-28
CN107400036B CN107400036B (en) 2019-09-20

Family

ID=60324673

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610335358.9A Active CN107400036B (en) 2016-05-19 2016-05-19 A method of synthesis 1,2- dimethylene cyclobutane chipal compounds

Country Status (2)

Country Link
CN (1) CN107400036B (en)
WO (1) WO2017197670A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110041371A (en) * 2018-01-17 2019-07-23 中国科学院福建物质结构研究所 Chiral metal rhodium complex, its synthetic method and its application in synthesis of chiral 1,5- dicarbonyl compound
CN110894187A (en) * 2018-09-12 2020-03-20 中国科学院福建物质结构研究所 Process for producing allene compound

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105294639A (en) * 2015-11-19 2016-02-03 中国科学院昆明植物研究所 Asymmetric cyclobutane derivatives, preparation method and applications thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105294639A (en) * 2015-11-19 2016-02-03 中国科学院昆明植物研究所 Asymmetric cyclobutane derivatives, preparation method and applications thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LATCHEZAR S. TRIFONOV ALEXANDER S. ORAHOVATS: "Intramolecular Cyclizations of Allenic Acylureas and ‐Amides", 《HELVETICA CHIMICA ACTA》 *
MASASHI HAMAGUCHI等: "Generation of Acyloxyketenes from Unstable Mesoionic 1,3-Dioxolium-4-olates and Their Reaction with Ketenophiles To Give [2+2] Cycloadducts", 《J.ORG.CHEM.》 *
XUEFENG JIANG等: "Controllable [2+2] Cycloadditions of 1,5-Bisallenyl-Substituted Compounds", 《ANGEWANDTE CHEMIE, INTERNATIONAL EDITION》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110041371A (en) * 2018-01-17 2019-07-23 中国科学院福建物质结构研究所 Chiral metal rhodium complex, its synthetic method and its application in synthesis of chiral 1,5- dicarbonyl compound
CN110894187A (en) * 2018-09-12 2020-03-20 中国科学院福建物质结构研究所 Process for producing allene compound
CN110894187B (en) * 2018-09-12 2021-04-06 中国科学院福建物质结构研究所 Process for producing allene compound

Also Published As

Publication number Publication date
CN107400036B (en) 2019-09-20
WO2017197670A1 (en) 2017-11-23

Similar Documents

Publication Publication Date Title
Krelaus et al. Preparation of peptide-like bicyclic lactams via a sequential Ugi reaction––olefin metathesis approach
Demirtas et al. Chiral calix [4] azacrowns for enantiomeric recognition of amino acid derivatives
JP6395714B2 (en) Ruthenium-based metathesis catalysts, precursors for their production and their use
CN105859622B (en) The method of palladium chtalyst asymmetric hydrogenation synthesis of chiral fluoro pyrazolone derivatives
Villeneuve et al. Ruthenium-catalyzed [2+ 2] cycloadditions of bicyclic alkenes and ynamides
CN109293468A (en) A method of it being catalyzed the decarboxylation coupling reaction synthesizing cis alkene of NHP ester and terminal aryl group alkynes by iridium
Malik et al. Ruthenium-catalyzed one-pot ring-closing metathesis/syn-dihydroxylation in the synthesis of bicyclic iminosugars
CN107400036B (en) A method of synthesis 1,2- dimethylene cyclobutane chipal compounds
CN106977486B (en) It is a kind of chirality flavanone kind composition and its derivative preparation method and application
Degtyareva et al. Application of Ni-based metal-organic framework as heterogeneous catalyst for disulfide addition to acetylene
Masui et al. Synthesis and structures of heterobimetallic Ir2M (M Pd, Pt) sulfido clusters and their catalytic activity for regioselective addition of alcohols to internal 1-aryl-1-alkynes
Langer et al. A new set of nickelacyclic carboxylates (“nickelalactones”) containing pyridine as supporting ligand: synthesis, structures and application in C–C–and C–S–linkage reactions
Sierra et al. Novel ferrocenylphosphino sulfonates: Synthesis, crystal structure and preliminary application as ligands in aqueous catalysis
Masoud et al. Synthesis of metathesis catalysts with fluorinated unsymmetrical N, N’-diaryl imidazoline-based NHC ligands
CN104592313B (en) Difunctional hydrogen bond organic catalyst based on ferrocene and its preparation method and application
Lang et al. Halfsandwich complexes of ruthenium (II), rhodium (III) and iridium (III) with N-substituted 3-hydroxy-2-methyl-4-pyridone ligands
CN109180682A (en) A kind of chiral aza ring carbene precursor compound and preparation method thereof with bicyclic skeleton
Balavoine et al. Preparation of electron-rich cationic ruthenium complexes of the type [(. eta. 5-C5Me5) Ru (bipyridine) L]+
Carmona et al. Asymmetric 1, 3-dipolar cycloaddition reaction of α, β-unsaturated nitriles with nitrones catalyzed by chiral-at-metal rhodium or iridium complexes
Behnke et al. Forskolin studies
Ghebreyessus et al. Carebene and isocyanide ligation at ruthenium (II) with (η6-arene) and tethered phosphinopropylarene ligands
Caro et al. Reactivity of carbanions of Fischer-type carbene complexes with pyrylium salts. Synthesis and characterization of new γ-methylenepyran carbene complexes via an addition–oxidation–deprotonation process
Steurer et al. Stereoselective synthesis of chiral, non-racemic 1, 2, 3-tri-and 1, 3-disubstituted ferrocene derivatives
CN109651421A (en) A kind of synthetic method of 2- aryl ortho position substitution triethyl group silicon pyridine compounds and their
CN104926747B (en) The preparation method and use of Huan Ji oxazolin ligands with optical activation

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant